Claims for Patent: 7,776,905

Summary for Patent: 7,776,905

Title:	Modulators of ATP-binding cassette transporters
Abstract:	Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
Inventor(s):	Sara S. Hadida Ruah, Peter D. J. Grootenhuis, Frederick Van Goor, Jinglan Zhou, Brian Bear, Mark T. Miller, Jason McCartney, Mehdi Michel Jamel Numa, Xiaoqing Yang
Assignee:	Vertex Pharmaceuticals Inc
Application Number:	US11/786,001
Patent Claims:	1. A compound selected from the group: 1 4 5 6 8 9 10 11 12 13 14 16 17 18 19 20 21 22 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 69 70 71 72 73 74 75 76 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 98 99 100 101 102 103 105 106 108 109 112 113 115 116 118 120 121 124 125 126 127 129 130 133 134 136 137 138 139 140 141 142 143 144 146 148 149 150 152 153 155 157 158 159 161 162 163 164 165 166 167 168 169 170 171 173 174 176 177 178 179 180 181 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 231 232 233 234 235 236 237 239 240 241 242 243 244 245 247 248 250 251 255 256 257 258 259 260 261 262 263 264 265 267 268 269 271 272 273 274 275 277 278 279 280 281 282 283 284 285 287 288 290 291 292 293 294 295 296 297 298 300 301 302 304 305 and 306 2. A pharmaceutical composition comprising a compound as described in claim 1 and a pharmaceutically acceptable carrier. 3. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising: (i) a composition comprising a compound according to claim 1; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuring activity of said ABC transporter or a fragment thereof. 4. The kit of claim 3, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound; and c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I). 5. The kit of claim 3, wherein the kit is used to measure the density of CFTR. 6. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein R1 is —ZAR4, wherein each ZA is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZA are optionally and independently replaced by —CO—, —CS—, —CONRA—, —CONRANRA—, —CO2—, —OCO—, —NRACO2—, —O—, —NRACONRA—, —OCONRA—, —NRANRA—, —NRACO—, —S—, —SO—, —SO2—, —NRA—, —SO2NRA—, —NRASO2—, or —NRASO2NRA—; Each R4 is independently RA, halo, —OH, —NH2, —NO2, —CN, or —OCF3; Each RA is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted aryl; n is 2 and the two R2 are adjacent to each other and together with the atoms to which they are attached form Ring A is an optionally substituted 3-7 membered monocyclic ring; Ring B is a group of the formula or a pharmaceutically acceptable salt thereof; wherein p is 0-2; Each R3 and R′3 is independently ZCR6, where each ZC is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by —CO—, —CS—, —CONRC—, CONRCNRC, —CO2—, —OCO—, —NRCCO2—, —O—, —NRCCONRC—, —OCONRC—, —NRCNRC—, —NRCCO—, —S—, —SO—, —SO2—, —NRC, —SO2NRC—, —NRCSO2—, or —NRCSO2NRC—; Each RC is independently RC, halo, —OH, —NH2, —NO2, —CN, or —OCF3; and Each RC is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted aryl; Or, any two adjacent R3 groups together with the atoms to which they are attached form an optionally substituted heterocycle. 7. The compound of claim 6, wherein R1 is —ZAR4, ZA is a bond, and R4 is hydrogen. 8. The compound of claim 6, wherein ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy, C1-5 aliphatic, or combinations thereof. 9. The compound of claim 6, wherein ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic. 10. The compound of claim 6, wherein ring A is one selected from wherein Each R9 is independently —ZER10, wherein each ZE is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZE are optionally and independently replaced by —CO—, —CS—, —CONRE—, —CO2—, —OCO—, —NRECO2—, —O—, —NRECONRE—, —OCONRE—, —NRENRE—, —NRECO—, —S—, —SO—, —SO2—, —NRE—, —SO2NRE—, —NRESO2—, or —NRESO2NRE—, Each R10 is independently RE, —OH, —NH2, —NO2, —CN, —CF3, oxo, or —OCF3, Each RE is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and q is 0-5. 11. The compound of claim 6, wherein R′3 is H. 12. The compound of claim 6, wherein one of R3 or R′3 is an optionally substituted acyl group. 13. The compound of claim 6, wherein one of R3 or R′3 is an (alkoxy)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. 14. The compound of claim 6, wherein one of R3 or R′3 is an (aliphatic)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. 15. The compound of claim 6, wherein one of R3 or R′3 is a (cycloaliphatic)carbonyl or a (heterocycloaliphatic)carbonyl, each is optionally substituted with 1-3 of aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof. 16. The compound of claim 15, wherein one of R3 or R′3 is (piperidine-1-yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, (morpholine-4-yl)carbonyl, (piperazine-1-yl)carbonyl, (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, or combinations thereof. 17. The compound of claim 6, wherein R3 is optionally substituted (aliphatic)amido that is attached to the 2 or 3 position on the indole ring of formula Ia. 18. The compound of claim 17, wherein R3 is (N,N-dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 19. The compound of claim 6, wherein R′3 is wherein R31 is H or a C1-2 aliphatic that is optionally substituted with 1-3 of halo, —OH, or combinations thereof, R32 is -L-R33, wherein L is a bond, —CH2—, —CH2O—, —CH2NHS(O)2—, —CH2C(O)—, —CH2NHC(O)—, or —CH2NH—, and R33 is hydrogen, or C1-2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally substituted with 1 of —OH, —NH2, or —CN. 20. The compound of claim 6, wherein R′3 is independently selected from one of the following: —H, —CH3, —CH2CH3, —C(O)CH3, —CH2CH2OH, —C(O)OCH3, 21. A pharmaceutical composition comprising a compound as described in claim 6 and a pharmaceutically acceptable carrier. 22. A kit for use in measuring the activity of an ABC transporter or a fragment thereof in a biological sample in vitro or in vivo, comprising: (i) a composition comprising a compound according to claim 6; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuring activity of said ABC transporter or a fragment thereof. 23. The kit of claim 22, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said ABC transporter or a fragment thereof in the presence of said additional compound; and c) comparing the activity of the ABC transporter in the presence of the additional compound with the density of the ABC transporter in the presence of a composition of formula (I). 24. The kit of claim 22, wherein the kit is used to measure the density of CFTR.